Modulation of redox-sensitive transcription factors with polyphenols as pathogenetically grounded approach in therapy of systemic inflammatory response.

One of the adverse outcomes of acute inflammatory response is progressing to the chronic stage or transforming into an aggressive process, which can develop rapidly and result in the multiple organ dysfunction syndrome. The leading role in this process is played by the Systemic Inflammatory Response that is accompanied by the production of pro- and anti-inflammatory cytokines, acute phase proteins, and reactive oxygen and nitrogen species. The purpose of this review that highlights both the recent reports and the results of the authors' own research is to encourage scientists to develop new approaches to the differentiated therapy of various SIR manifestations (low- and high-grade systemic inflammatory response phenotypes) by modulating redox-sensitive transcription factors with polyphenols and to evaluate the saturation of the pharmaceutical market with appropriate dosage forms tailored for targeted delivery of these compounds.

Production of fever mediator PGE in human monocytes activated with MDP adjuvant is controlled by signaling from MAPK and p300 HAT: Key role of T cell derived factor.

Fever and inflammatory responses were observed in some subjects in early clinical trials of vaccines adjuvanted with muramyl dipeptide (MDP), a NOD2 agonist. Biosynthesis of Prostaglandin E2 (PGE) that transmits febrile signals to the brain is controlled by an inducible enzyme, Cyclooxygenase 2 (COX-2). MDP alone was not sufficient to induce expression of COX-2 and PGE production in vitro.

T cell-derived soluble glycoprotein GPIbα mediates PGE production in human monocytes activated with the vaccine adjuvant MDP.

Vaccine adjuvants containing analogs of microbial products activate pattern recognition receptors (PRRs) on antigen-presenting cells, including monocytes and macrophages, which can cause prostaglandin E (PGE) release and consequently undesired inflammatory responses and fever in vaccine recipients. Here, we studied the mechanism of PGE production by human monocytes activated with muramyl dipeptide (MDP) adjuvant, which activates cytosolic nucleotide-binding oligomerization domain 2 (NOD2). In rabbits, administration of MDP elicited an early increase in PGE followed by fever.

Differences in PGE2 production between primary human monocytes and differentiated macrophages: role of IL-1β and TRIF/IRF3.

Prostaglandin E2 (PGE2) is induced in vivo by bacterial products including TLR agonists. To determine whether PGE2 is induced directly or via IL-1β, human monocytes and macrophages were cultured with LPS or with Pam3CSK4 in presence of caspase-1 inhibitor, ZVAD, or IL-1R antagonist, Kineret. TLR agonists induced PGE2 in macrophages exclusively via IL-1β-independent mechanisms.

Use of human MonoMac6 cells for development of in vitro assay predictive of adjuvant safety in vivo.

Subunit vaccines composed of recombinant or purified antigens have a good safety record but are poorly immunogenic and require adjuvants to activate innate immunity and facilitate antigen specific immune response. Of the many adjuvant formulations that are under development, very few are licensed mainly due to concerns about adverse side effects. The goal of our study was to develop in vitro assays that could predict toxicity of adjuvants in vivo.